Levomilnacipran is the international nonproprietary name for (1S,2R)-2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide. It is a highly potent selective norepinephrine (NE) and serotonin (5-HT) reuptake inhibitor with greater selectivity for NE reuptake inhibition than for 5-HT reuptake inhibition. In particular, levomilnacipran has an inhibitory selectivity ratio for NE:5-HT of approximately 1.5:1. Accordingly, levomilnacipran is considered a norepinephrine-serotonin reuptake inhibitor (NSRI) that is pharmacologically distinct from serotonin-norepinephrine reuptake inhibitors (SNRI) having equal or higher inhibitory selectivity for 5-HT than for NE.
While formulations of levomilnacipran are generally discussed in the prior art, difficulties have been encountered in preparing stable dosage forms of levomilnacipran. These difficulties have arisen, at least in part, due to the sensitivity of levomilnacipran to certain reaction conditions and its reactivity with certain commonly-used excipients.
Accordingly, there is an existing and continual need for improved formulations of levomilnacipran having improved purity and stability. In addition, the improved-stability formulations must achieve a desirable pharmacokinetic profile that is associated with a low incidence of undesirable adverse events (for example, nausea, vomiting and gastric bleeding) in patients.
Improved formulations of levomilnacipran have now been discovered which achieve a desirable release of levomilnacipran upon entering a use environment and which have surprisingly high stability. These improved formulations of levomilnacipran are described herein.